N-methyl d-glucamine salt of 2(2&#39;-methyl-3&#39;-trifluoromethylanilino)nicotinic acid

ABSTRACT

1. THE N-METHYL-D-GLUCAMINE SALT OR 2(2&#39;&#39;-,ETHYL-3&#39;&#39;-TRIFLURROMETHYLANILINO) NICOTINIC ACID.

United States Patent 3,839,344 N-METHYL D-GLUCAMINE SALT 0F 2(2'-METHYL- Z'C-IDTRIFLUOROMETHYLANILINO) NICOTINIC Margaret H. Sherlock, Bloomfield, N.J., assiguor to Schering Corporation, Bloomfield, N.J. No Drawing. Filed Mar. 28, 1973, Ser. No. 345,608 Int. Cl. 'C07d 31/36 U.S. Cl. 260-295.5 R 1 Claim ABSTRACT OF THE DISCLOSURE This invention relates to the N-methyl-D-glucamine salt of 2-(2'-methyl- '-trifluoromethylanilino) nicotinic acid and to its particular suitability as a parenterally administered analgesic agent.

This invention relates to the N-methyl-D-glucamine salt of 2-(2'-methyl-3'-trifluoromethylanilino)nicotinic acid, to its preparation, and to its use as a potent analgesic, particularly suitable for parenteral administration.

It is well known that certain substituted anilino nicotinic acids, and salts thereof, are useful as analgesic/antiinflammatory agents. Indeed, as described in U.S. Pats. 3,337,570 and 3,689,653 and in Belgian Pat. 679,271, the preparation and properties of such compounds are well-described. Quite unexpectedly, I have discovered that the N-methyl glucamine salt of a particular compound of this group is a potent analgesic particularly suitable for parenteral administration.

According to standard rat yeast paw tests it has been found upon comparison with its free acid or sodium salt, that the N-methyl-D-glucamine salt of 2-(2'-methy1-3'- triifluoromethyl anilino) nicotinic acid was the only compound which produced marked analgesic activity after subcutaneous administration, such that neither the 2-(2'-methyl-3'-trifluoromethylanilino) nicotinic acid per se or its sodium salt produced comparable analgesic activity even at doses four times that of the N-methyl-D-glucamine salt. The foregoing factor being in marked contrast to the showing that the N-methyl-D-glucamine salt of either 2-(2-methyl-3-chloroanilino) nicotinic acid or 2-(3-trifluoromethylanilino) nicotinic acid did not exhibit any such activity. Also in contrast, the N-methyl-D-glucamine salt of 2-(2-methyl- -trifiuoromethylanilino) nicotinic acid and of 2-(2-methyl-3'-chloroanilino) nicotinic acid are virtually equipotent when compared to their respective free acid after oral administration. Thus, the N-methyl-D- glucamine salt of 2-(2'-methyl-3-trifluoromethylanilino) nicotinic acid has unique parenteral activity with a potency comparable to that seen by potent narcotic analgesics such as morphine and the like. Indeed, when compared either on its analgesic potency or on its relative freedom from undesirable side effects, the N-methyl-D-glucamine salt of 2-(2'-methyl-3'-trifluoromethylanilino) nicotinic acid is more advantageously applied than such drugs as morphine, meperidine hydrochloride, and pentazocine; it being well known that such compounds possess very valuable and useful analgesic properties. Thus, the N-methyl-D- glucamine salt of 2-(2'-methyl- '-trifluoromethyl) nicotinic acid is particularly suitable as a parenterally administered analgesic in clinical and veterinary applications for those conditions wherein such prior art compounds would normally be indicated. In such instances the dose, as determined by standard assay techniques, would be 0.25 to milligrams per kilogram of body weight parenterally (i.e., intravenously, subcutaneously or intramuscularly) administered. In addition to its parenteral analgesic properties, the compound of this application also possesses antiinflammatory properties.

3,839,344 Patented Oct. 1, 1974 The preparation of the compounds of this invention are as follows:

CHEMICAL PREPARATIONS A. 2(2-Methyl-3'-trifluoromethylanilino) nicotinic acid To 20 g. of 2-methyl-3-trifluoromethyl aniline heated at 200, add, in a dropwise fashion, 11 g. of ethyl 2-chloronicotinate. Heat the reaction mixture of 200 for one-half hour, cool, pour the mixture onto ice and extract with ether. Concentrate the ester extracts, dry and fractionate the residue in vacuo; b.p. 143146/0.15 mm.; m.p. 44- 46.

To a solution of 12 g. of ethyl (2-2'-methyl-3'-trifluoromethylanilino)nicotinate in m1. of methanol and 4.6 g. of potassium hydroxide in 10 ml. of water. Reflux the solution for three hours, concentrate in vacuo and dissolve the residue in water. Acidify the aqueous solution to yield the desired 2(2-methyl-3'-trifluoromethylanilino) nicotinic acid, m.p. 226228 C. after recrystallization from ace tone-hexane.

B. N-Methyl-D-glucamine salt A mixture of 15 g. of 2(2-methy1-3-trifluoromethy1- anilino) nicotinic acid and 10.5 g. of N-methyl glucamine was dissolved in 70 ml. of hot ethanol. On dilution with 300 ml. of ether, the salt separated as colorless crystals, m.p. 137. (Can be recrystallized from acetonitrile or ethanol-ether, m.p. 136-139.)

PHARMACEUTICAL FORMULATION PREPARATIONS A. Intramuscular/ Subcutaneous Formula Mg./ml.

N-methyl-D-glucamine salt of 2(2 methyl-3'- trifiuoromethylanilino) nicotinic acid 10-150 Disodium Edetate, USP 0.1 Formopon 2.5 Phenol, Crystalline Mallinckrodt, AR 5.0 Diethanolamine 4.0 100.0

Propylene Glycol, U.S.P. HCl 2.0 Normal q.s. to pH 8.5. Water for Injection q.s. to 1.0 ml.

1 Base equivalent.

Procedure Mg./ml.

N-methyl-D-glucamine salt of 2(2-methyl-3-trifiuoromethylanilino) nicotinic acid 1 10-150 Disodium Edetate, USP 0.1 Sodium Bisulfite, USP 1.625 Benzyl Alcohol, NF 15.0

Sodium Hydroxide 1.0 Normal q.s. to pH 8.5. Water for Injection, USP q.s. to 1.0 ml.

1 Base equivalent.

3 4 Procedure I claim:

1. The N-methyl-D-glucamine salt of 2(2-methyl-3'-tri- Charge about 80-85% of the Water of Injection into a fluoromethylanilino) nicotinic acid. suitable compounding vessel and sparge with nitrogen for 10 minutes. Add and dissolve separately with agitation 5 References Cited While sparging, in order, the following ingredients: benzyl FOREIGN PATENTS alcohol, disodium edetate, and sodium bisulfite. Discontinue nitrogen sparging and adjust the pH to 8.5 with 1.0 210 7/1968 France 260-2956 R Normal sodium hydroxide solution. Dissolve with agita- OTHER REFERENCES tion the N-methyl-D-glucamine salt of 2(2'-methy1-3- 10 Evans et al., Journal of Medicinal Chemistry, vol. 10 trifluoromethylanilino) nicotinic acid and bring the solu- (3) pp. 428-31 (1967).

tion to final volume. Aseptically filter the solution through a suitable sterilizing membrane equipped with prefilter. ALAN ROTMAN Pnmary Exammer Fill the required amount into appropriate sterile con- US. Cl. X,R

tainers. 424-266 

1. THE N-METHYL-D-GLUCAMINE SALT OR 2(2''-,ETHYL-3''-TRIFLURROMETHYLANILINO) NICOTINIC ACID. 